Ginkgolide b derivative and salt thereof, preparation method therefor and use thereof

ABSTRACT

The present invention relates to the technical field of medicine, and to derivatives represented by formula 1 and formula 2 in which a carboxylic acid group is introduced into the structure of Ginkgolide B by means of a hydroxyl group at the 10-position and ester derivatives of carboxylic acid groups, and pharmaceutically acceptable organic or inorganic salts. Ginkgolide B is used as a parent body and is prepared by means of chemical structure modification so as to achieve the goals of improving solubility, increasing bioavailability and enhancing healing efficacy. The prepared compound and carboxylate salts thereof have significant platelet activating factor antagonism, an anticoagulant effect and an anti-acute cerebral ischemia effect, and can be used for preparing a drug for preventing and treating ischemic stroke, thrombosis, angina pectoris, cardiopulmonary infarction, as well as inflammation, asthma and other diseases related to a platelet activating factor.

The present application claims the priority of Chinese patentapplication CN201910338234.X filed on Apr. 24, 2019. This applicationrefers to the full text of the above-mentioned Chinese patentapplication.

TECHNICAL FIELD

The present disclosure belongs to the technical field of medicine, andrelates to Ginkgolide B carboxylic acid derivatives and esters thereof,and the corresponding salts of Ginkgolide B carboxylic acid derivatives,and specifically relates to Ginkgolide B carboxylic acid derivatives andesters thereof and preparation methods therefor and uses thereof. Thepresent disclosure uses Ginkgolide B as a parent body, and theGinkgolide B derivatives are prepared by chemical structuremodification, so as to achieve the purposes of changing the solubility,improving the bioavailability and enhancing the curative effect.

BACKGROUND

It has been recorded that Ginkgo biloba was used in our folklore around1000 AD to treat asthma and bronchitis. In recent times, with thestandardization of drug extraction process and in-depth research onpharmacological action activity, Ginkgo biloba extract (GBE) has beenwidely used in the world, especially in Germany, France and otherEuropean countries for the treatment of diseases such as respiratorysystem and cardiovascular system.

The prior art discloses that Ginkgolide B (GB) is a diterpenoid compoundextracted from Ginkgo biloba; biological activity evaluation shows thatGinkgolide B is the most active natural product of platelet activatingfactor (PAF) antagonist found to date. Platelet activating factor canpromote the aggregation of platelets and neutrophils, and participate invarious inflammatory reaction processes, thereby increasing vascularpermeability, promoting thrombosis and inducing smooth musclecontraction, and playing an important role in the occurrence anddevelopment of a series of related diseases such as inflammation,asthma, cardiovascular and cerebrovascular microcirculation disturbance,gastrointestinal mucosal damage, etc. At the same time, studies havefound that Ginkgolide B also has a strong anti-inflammatory effect. Inthe inflammatory reaction, the phospholipid of neutrophil membrane ishydrolyzed into arachidonic acid (AA) by LPA of activated phospholipaseA2, and AA is further metabolized into products such as leukotrienes(LTs) and hydroxyeicosatetraenoic acid (HETEs) under the action of5-lipoxygenase (5-LO), wherein some products are important inflammatorymediators, and the activation of phospholipase A2 requires theparticipation of intracellular calcium, ginkgolide B has an effect onarachidonic acid metabolic enzyme and intracellular free calcium in ratneutrophils, and its anti-inflammatory effect may be related to itsinhibition of lysosomal enzyme release in neutrophils, production ofsuperoxide anion and increase of intracellular calcium level.

At present, the varieties of Ginkgolide drugs in clinical use mainlyinclude two categories of Ginkgolide mixed extracts including GinkgolideB components and Ginkgolide B as the main component, which are mainlyused for the treatment of thrombosis, acute pancreatitis andcardiovascular diseases, and the treatment of metastatic cancer, theprotective effect on damaged neurons, etc. However, practice shows thatGinkgolide B has strong structural rigidity, poor water solubility andpoor bioavailability due to its six-ring cage-like structuralcharacteristics of diterpenoid compounds, which limits the full play ofits efficacy and affects its clinical use effect.

Based on the current state of the prior art, the inventors of thepresent disclosure intend to provide Ginkgolide B carboxylic acidderivatives and esters thereof and preparation methods therefor and usethereof. The present disclosure uses Ginkgolide B as a parent body, andthe Ginkgolide B derivative is prepared by chemical structuremodification, so as to achieve the purposes of changing its watersolubility, improving the bioavailability and enhancing the curativeeffect.

CONTENT OF THE PRESENT INVENTION

The purpose of the present disclosure is to provide a new class ofGinkgolide B carboxylic acid derivatives and esters thereof, and theGinkgolide B carboxylic acid derivatives may be made into correspondingorganic bases or inorganic base salts. The present disclosure obtains anew class of Ginkgolide B carboxylic acid derivatives and esters thereofthrough structural modification of Ginkgolide B by introducing variousgroup containing carboxyl and ester groups thereof on hydroxyl at the10-position, which may improve the solubility and overcome theunfavorable factors such as poor bioavailability of Ginkgolide B.

The present invention provides a compound represented by formula 1,

wherein,

L is heteroatom, substituted or unsubstituted C₁₋₁₀ hydrocarbonylene,substituted or unsubstituted C₁₋₁₀ heterohydrocarbonylene containingheteroatoms, or not existed; when L is heteroatom or substituted orunsubstituted C₁₋₁₀ heterohydrocarbonylene containing heteroatoms, theheteroatoms are selected from one or more of oxygen, nitrogen andsulfur; when there are multiple heteroatoms, the heteroatoms are thesame or different;

R is hydrogen or substituted or unsubstituted C₁₋₈ hydrocarbonyl;

wherein the substituent in the substituted C₁₋₁₀ hydrocarbonylene, thesubstituted C₁₋₁₀ heterohydrocarbonylene containing heteroatoms and thesubstituted C₁₋₈ hydrocarbonyl is independently one or more of halogen,hydroxyl, C₁₋₁₀ alkoxy, phenyl and C₁₋₁₀ alkyl, and when multiplesubstituents exist, the substituents are the same or different;

The compound represented by formula 1 is not:

In a preferred embodiment of the present disclosure, when thesubstituent in the substituted C₁₋₁₀ hydrocarbonylene, the substitutedC₁₋₁₀ heterohydrocarbonylene containing heteroatoms and the substitutedC₁₋₈ hydrocarbonyl is halogen, the halogen is preferably fluorine,chlorine, bromine or iodine.

In a preferred embodiment of the present disclosure, when thesubstituent in the substituted C₁₋₁₀ hydrocarbonylene, the substitutedC₁₋₁₀ heterohydrocarbonylene containing heteroatoms and the substitutedC₁₋₈ hydrocarbonyl is C₁₋₁₀ alkoxy, the C₁₋₁₀ alkoxy is preferably C₁₋₄alkoxy, more preferably methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy or tert-butoxy.

In a preferred embodiment of the present disclosure, when thesubstituent in the substituted C₁₋₁₀ hydrocarbonylene, the substitutedC₁₋₁₀ heterohydrocarbonylene containing heteroatoms and the substitutedC₁₋₈ hydrocarbonyl is C₁₋₁₀ alkyl, the C₁₋₁₀ alkyl is preferably C₁₋₄alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl.

In the present disclosure, the term hydrocarbonylene refers to a groupcontaining two types of atoms of carbon and hydrogen, and is the groupremaining after the loss of any two hydrogen atoms from thecorresponding hydrocarbon. The term hydrocarbonylene is preferablyalkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene,cycloalkynylene or arylene.

In the present disclosure, the term alkenylene refers to chainalkenylene, wherein the number of carbon-carbon double bonds is one ormore, and the carbon-carbon double bonds may be located at any positionof chain alkenylene.

In the present disclosure, the term alkynylene refers to chainalkynylene, wherein the number of carbon-carbon triple bonds is one ormore, and the carbon-carbon triple bonds may be located at any positionof chain alkynylene.

In the present disclosure, the term cycloalkenylene refers to cyclicalkenylene, wherein the number of carbon-carbon double bonds is one ormore, and the carbon-carbon double bonds may be located at any positionof cyclic alkenylene.

In the present disclosure, the term cycloalkynylene refers to cyclicalkynylene, wherein the number of carbon-carbon triple bonds is one ormore, and the carbon-carbon triple bonds may be located at any positionof cyclic alkynylene.

In the present disclosure, the term hydrocarbonyl refers to a groupcontaining two types of atoms of carbon and hydrogen, and is the groupremaining after the loss of any one hydrogen atom from the correspondinghydrocarbon. The term hydrocarbonyl is preferably alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl or aryl.

In the present disclosure, the term alkenyl refers to chain alkenyl,wherein the number of carbon-carbon double bonds is one or more, and thecarbon-carbon double bonds may be located at any position of chainalkenyl.

In the present disclosure, the term alkynyl refers to chain alkynyl,wherein the number of carbon-carbon triple bonds is one or more, and thecarbon-carbon triple bonds may be located at any position of chainalkynyl.

In the present disclosure, the term cycloalkenyl refers to cyclicalkenyl, wherein the number of carbon-carbon double bonds is one ormore, and the carbon-carbon double bonds may be located at any positionof cyclic alkenyl.

In the present disclosure, the term cycloalkynyl refers to cyclicalkynyl, wherein the number of carbon-carbon triple bonds is one ormore, and the carbon-carbon triple bonds may be located at any positionof cyclic alkynyl.

In the present disclosure, the term heteroalkyl refers to thehydrocarbonylene of the present disclosure containing one or moreheteroatoms inserted at any position. Wherein, the hydrocarbonylene isas defined above.

In the present disclosure, the term chain includes straight chain andbranched chain.

In the present disclosure, the term cycloalkyl is preferably C₃-C₁₀cycloalkyl, more preferably C₃-C₆ cycloalkyl. Examples of cycloalkylinclude, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

In the present disclosure, the term aryl is preferably C₆-C₁₀ aryl.Examples of aryl include, but are not limited to: phenyl, naphthyl, ortetrahydronaphthyl.

In the present disclosure, the term heteroarylene is preferably C₁-C₁₀heteroarylene containing 1, 2, 3 or 4 heteroatoms selected from O, N andS, further preferably C₁-C₈ heteroarylene containing 1, 2, 3 or 4heteroatoms selected from O, N and S, and more preferably C₁-C₆heteroarylene containing 1, 2, 3 or 4 heteroatoms selected from O, N andS.

In the present disclosure, the term alkyl includes branched and straightchain saturated aliphatic hydrocarbonyl, preferably containing 1-10carbon atoms. Examples of alkyl include but are not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl,2,2,4-trimethylpentyl, and various isomers thereof.

In the present disclosure, the alkyl is preferably C₁-C₄ alkyl, morepreferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert-butyl.

In a preferred embodiment of the present disclosure, the C₁₋₁₀hydrocarbonylene in the “substituted or unsubstituted C₁₋₁₀hydrocarbonylene” is preferably C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀alkynylene, C₃₋₁₀ cycloalkylene, C₃₋₁₀ cycloalkenylene, C₄₋₁₀cycloalkynylene, phenylene or naphthylene.

In a preferred embodiment of the present disclosure, the C₁₋₁₀hydrocarbonylene in the “substituted or unsubstituted C₁₋₁₀hydrocarbonylene” is preferably C₃₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀alkynylene, C₃₋₁₀ cycloalkylene, C₃₋₁₀ cycloalkenylene, C₄₋₁₀cycloalkynylene, phenylene or naphthylene.

In a preferred embodiment of the present disclosure, the C₁₋₁₀heterohydrocarbonylene in the “substituted or unsubstituted C₁₋₁₀heterohydrocarbonylene containing heteroatoms” is preferably C₁₋₁₀heteroalkylene, C₂₋₁₀ heteroalkenylene, C₂₋₁₀ heteroalkynylene, C₂₋₁₀heterocycloalkylene, C₂₋₁₀ heterocycloalkenylene, C₂₋₁₀ heteroalkenyleneor C₁₋₁₀ heteroarylene.

In a preferred embodiment of the present disclosure, the C₁₋₈hydrocarbonyl in the “substituted or unsubstituted C₁₋₈ hydrocarbonyl”is preferably C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, C₄₋₈ cycloalkenyl or phenyl.

In a preferred embodiment of the present disclosure, the L is preferablyheteroatom, substituted or unsubstituted C₁₋₁₀ alkylene, substituted orunsubstituted C₂₋₁₀ alkenylene, substituted or unsubstituted C₂₋₁₀alkynylene, substituted or unsubstituted C₃₋₁₀ cycloalkylene,substituted or unsubstituted C₃₋₁₀ cycloalkenylene, substituted orunsubstituted C₄₋₁₀ cycloalkynylene, substituted or unsubstitutedphenylene, substituted or unsubstituted naphthylene, substituted orunsubstituted C₁₋₁₀ heteroalkylene, substituted or unsubstituted C₂₋₁₀heteroalkenylene, substituted or unsubstituted C₂₋₁₀ heteroalkynylene,substituted or unsubstituted C₂₋₁₀ heterocycloalkylene, substituted orunsubstituted C₂₋₁₀ heterocycloalkenylene, substituted or unsubstitutedC₂₋₁₀ heterocycloalkynylene, substituted or unsubstituted C₁₋₁₀heteroarylene, or not existed.

In a preferred embodiment of the present disclosure, the R is preferablyhydrogen, methyl, benzyl, substituted or unsubstituted C₃₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, substitutedor unsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstituted C₄₋₈cycloalkynyl, or substituted or unsubstituted phenyl.

In a preferred embodiment of the present disclosure, when the L is aheteroatom, the heteroatom is preferably oxygen or sulfur.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₁₋₁₀ alkylene, the C₁₋₁₀ alkylene in the“substituted or unsubstituted C₁₋₁₀ alkylene” is preferably C₁₋₈alkylene, further preferably methylene, ethylene, n-propylene,isopropylene, n-butylene, tert-butylene, or n-pentylene.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ alkenylene, the C₂₋₁₀ alkenylene inthe “substituted or unsubstituted C₂₋₁₀ alkenylene” is preferably C₂₋₅alkenylene, more preferably vinylene, propylene, butylene orpentenylene, further more preferably vinylene, and most preferably—CH═CH—.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ alkynylene, the C₂₋₁₀ alkynylene inthe “substituted or unsubstituted C₂₋₁₀ alkynylene” is preferably C₂₋₅alkynylene, and more preferably ethynylene, propynylene, butynylene orpentynylene.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₃₋₁₀ cycloalkylene, the C₃₋₁₀cycloalkylene in the “substituted or unsubstituted C₃₋₁₀ cycloalkylene”is preferably C₃₋₈ cycloalkylene, further preferably cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene orcyclooctylene.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₃₋₁₀ cycloalkenylene, the C₃₋₁₀cycloalkenylene in the “substituted or unsubstituted C₃₋₁₀cycloalkenylene” is preferably C₃₋₈ cycloalkenylene, further preferablycyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene,cycloheptenylene or cyclooctenylene.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₁₋₁₀ heteroalkylene containingheteroatoms, the C₁₋₁₀ heteroalkylene in the “substituted orunsubstituted C₁₋₁₀ heteroalkylene containing heteroatoms” is preferablyC₁₋₆ heteroalkylene, further preferably C₁₋₄ heteroalkylene, furthermore preferably heteromethylene, heteroethylene, heteropropylene,heteroisopropylene, hetero-n-butylene, heteroisobutylene orhetero-tert-butyl, still further preferably heteroethylene orhetero-tert-butyl, wherein the heteroatom is preferably oxygen orsulfur, the number of heteroatoms is preferably 1 or 2, and the C₁₋₁₀heteroalkylene is most preferably —CH₂OCH₂— or —CH₂OCH₂CH₂OCH₂—.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ heteroalkenylene, the C₂₋₁₀heteroalkenylene in the “substituted or unsubstituted C₂₋₁₀heteroalkenylene” is preferably C₂₋₅ heteroalkenylene, furtherpreferably heterovinylene, heteropropenylene, heterobutenylene orheteropentenylene, wherein the heteroatom is preferably oxygen orsulfur, and the number of heteroatoms is preferably 1 or 2, and theC₂₋₁₀ heteroalkenylene is most preferably —CH═CH—O—CH₂—, —CH═CH—O—,—CH₂OCH═CHOCH₂— or —CH═CH—S—CH₂—.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ heteroalkynylene, the C₂₋₁₀heteroalkynylene in the “substituted or unsubstituted C₂₋₁₀heteroalkynylene” is preferably C₂₋₄ heteroalkynylene, furtherpreferably heteroethynylene, heteropropynylene, heterobutynylene orheteropentynylene, wherein the heteroatom is preferably oxygen orsulfur, and the number of heteroatoms is preferably 1 or 2, and theC₂₋₁₀ heteroalkynylene is most preferably —C≡C—O—CH₂—, —C≡C—O—,—CH₂OC≡COCH₂— or —C≡C—S—CH₂—.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ heterocycloalkylene, the C₂₋₁₀heterocycloalkylene in the “substituted or unsubstituted C₂₋₁₀heterocycloalkylene” is preferably C₂₋₅ heterocycloalkylene, furthermore preferably heterocycloethylene, heterocyclopropylene,heterobutylene or heteropentylene, wherein the heteroatom is preferablyoxygen or sulfur, and the number of heteroatoms is preferably 1 or 2.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₂₋₁₀ heterocycloalkenylene, the C₂₋₁₀heterocycloalkenylene in the “substituted or unsubstituted C₂₋₁₀heterocycloalkenylene” is preferably C₂₋₅ heterocycloalkenylene, furtherpreferably heterocyclovinylene, heterocyclopropenylene,heterocyclobutenylene or heterocyclopentenylene, wherein, the heteroatomis preferably oxygen or sulfur, and the number of heteroatoms ispreferably 1 or 2.

In a preferred embodiment of the present disclosure, when the L issubstituted or unsubstituted C₁₋₁₀ heteroarylene, the C₁₋₁₀heteroarylene in the “substituted or unsubstituted C₁₋₁₀ heteroarylene”is preferably C₁₋₉ heteroarylene, wherein the heteroatom is preferablyoxygen or nitrogen, and the number of heteroatoms is preferably 1, 2, 3or 4.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₁₋₈ alkyl, the C₁₋₈ alkyl in the“substituted or unsubstituted C₁₋₈ alkyl” is preferably n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₃₋₈ alkyl, the C₃₋₈ alkyl in the“substituted or unsubstituted C₃₋₈ alkyl” is preferably n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₂₋₈ alkenyl, the C₂₋₈ alkenyl in the“substituted or unsubstituted C₂₋₈ alkenyl” is preferably C₂₋₅ alkenyl,further preferably vinyl, propenyl, butenyl or pentenyl.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₂₋₈ alkynyl, the C₂₋₁₀ alkynyl in the“substituted or unsubstituted C₂₋₈ alkynyl” is preferably C₂₋₅ alkynyl,further preferably ethynyl, propynyl, butynyl or pentynyl.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₃₋₈ cycloalkyl, the C₃₋₈ cycloalkyl in the“substituted or unsubstituted C₃₋₈ cycloalkyl” is preferablycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl.

In a preferred embodiment of the present disclosure, when the R issubstituted or unsubstituted C₃₋₈ cycloalkenyl, the C₃₋₈ cycloalkenyl inthe “substituted or unsubstituted C₃₋₈ cycloalkenyl” is preferablycyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenylor cyclooctenyl.

In a preferred embodiment of the present disclosure, the L is preferablysubstituted or unsubstituted C₂₋₁₀ alkenylene, substituted orunsubstituted C₁₋₁₀ heteroalkylene, or not existed.

In a preferred embodiment of the present disclosure, the R is preferablyhydrogen, methyl, benzyl, or substituted or unsubstituted C₃₋₈ alkyl.

In a preferred embodiment of the present disclosure, the L is preferably—CH═CH—, —CH₂OCH₂—, —CH₂OCH₂CH₂OCH₂— or L is not existed.

In a preferred embodiment of the present disclosure, the R is preferablyhydrogen, methyl or tert-butyl.

In a preferred embodiment of the present disclosure, the compoundrepresented by formula 1 or the pharmaceutically acceptable salt thereofis selected from any of the following compounds:

The present disclosure also provides a compound represented by formula2:

Wherein, L is as defined above;

cations, including cations formed from various inorganic and organicbases; the cations formed from inorganic bases may preferably beselected from sodium, potassium, calcium, magnesium, zinc, or ammoniumcations etc., but are not limited to these salts; the cations formedfrom organic bases may preferably be selected from primary aminescontaining substituted or unsubstituted C₁₋₈ hydrocarbonyl, secondaryamines containing substituted or unsubstituted C₁₋₈ hydrocarbonyl,nitrogen positive cations formed from tertiary amines containingsubstituted or unsubstituted C₁₋₈ hydrocarbonyl, and nitrogen positivecations formed from natural or non-natural amino acids, but are notlimited to these salts.

In the present disclosure, the primary amine containing substituted orunsubstituted C₁₋₈ hydrocarbonyl refers to an amine formed bysubstituting a hydrogen atom on the ammonia with a substituted orunsubstituted C₁₋₈ hydrocarbonyl; wherein the substituted orunsubstituted C₁₋₈ hydrocarbonyl is as described above.

In the present disclosure, the secondary amine containing substituted orunsubstituted C₁₋₈ hydrocarbonyl refers to an amine formed bysubstituting two hydrogen atoms on the ammonia with two substituted orunsubstituted C₁₋₈ hydrocarbonyl, respectively, the two substituted orunsubstituted C₁₋₈ hydrocarbonyl may be the same or different, and thetwo substituted or unsubstituted C₁₋₈ hydrocarbonyl may form a ring ineither manner (as long as it does not violate the common sense in theart), forming a ring such as pyrrolidine, piperidine, morpholine orthiomorpholine, etc.; wherein the substituted or unsubstituted C₁₋₈hydrocarbonyl is as described above.

In the present disclosure, the tertiary amine containing substituted orunsubstituted C₁₋₈ hydrocarbonyl refers to an amine formed bysubstituting three hydrogen atoms on the ammonia with three substitutedor unsubstituted C₁₋₈ hydrocarbonyl, the three substituted orunsubstituted C₁₋₈ hydrocarbonyl may be the same or different, and twoor three substituted or unsubstituted C₁₋₈ hydrocarbonyl among the threesubstituted or unsubstituted C₁₋₈ hydrocarbonyl may form a ring ineither manner (as long as it does not violate the common sense in thefield); wherein, the substituted or unsubstituted C₁₋₈ hydrocarbonyl isas described above.

In the present disclosure, the natural or non-natural amino acids arethose various types of amines containing carboxyl groups on theirhydrocarbon chain, preferably L-arginine, L-histidine, L-lysine,D-arginine, D-histidine, D-lysine.

In a preferred embodiment of the present disclosure, the inorganic basein the cations formed by various inorganic bases and organic bases ispreferably sodium carbonate, sodium bicarbonate, sodium hydroxide,potassium carbonate, calcium hydroxide, magnesium carbonate, magnesiumhydroxide, ammonium hydroxide or zinc hydroxide.

In a preferred embodiment of the present disclosure, the organic base inthe cations formed by various inorganic bases and organic bases may beamine compound, or natural or non-natural amino acid compound. The aminecompounds are particularly preferably methylamine, dimethylamine,trimethylamine, ethylamine, diethylamine, triethylamine, propylamine,butylamine, pentylamine, hexylamine, N-methyl-D-glucosamine,pyrrolidine, morpholine and thiomorpholine. The amino acid compounds arepreferably L-lysine, L-histidine, L-arginine, D-lysine, D-histidine andD-arginine.

In a preferred embodiment of the present disclosure, the cation in thecompound represented by formula 2 is preferably

In a preferred embodiment of the present disclosure, the compoundrepresented by formula 2 is selected from any of the followingcompounds:

The present disclosure also provides a method for preparing a compoundrepresented by formula 1 or a pharmaceutically acceptable salt thereof,comprising the following steps:

In an organic solvent, under the action of a base and a catalyst,Ginkgolide B and the compound represented by formula 3 are subjected tothe ether-forming reaction as shown below to obtain the compoundrepresented by formula 1,

wherein, R and L are as defined above, and X is halogen.

In the ether-forming reaction, the X is preferably fluorine, chlorine,bromine or iodine, further preferably chlorine, bromine or iodine.

In the ether-forming reaction, the organic solvent may be an organicsolvent conventional in the art for this type of reaction, the organicsolvent in the present disclosure is particularly preferably one or moreof halogenated hydrocarbon solvents, ether solvents, ketone solvents,nitrile solvents and amide solvents. The halogenated hydrocarbon solventis preferably dichloromethane and/or chloroform. The ether solvent ispreferably tetrahydrofuran and/or dioxane, and more preferablytetrahydrofuran. The ketone solvent is preferably acetone and/orbutanone. The nitrile solvent is preferably acetonitrile. The amidesolvent is preferably N,N-dimethylformamide.

In the ether-forming reaction, the base may be a base conventional inthe art for this type of reaction, such as organic base and/or inorganicbase. The organic base is preferably amine organic base, and morepreferably one or more of triethylamine, pyrrolidine and piperazine. Theinorganic base is preferably carbonate and/or bicarbonate. The carbonateis preferably one or more of sodium carbonate, potassium carbonate andcesium carbonate. The bicarbonate is preferably sodium bicarbonate.

In the ether-forming reaction, the catalyst may be a catalystconventional in the art for this type of reaction, the catalyst in thepresent disclosure is particularly preferably iodide, further preferablyone or more of potassium iodide, sodium iodide and cuprous iodide, andmost preferably potassium iodide.

In the ether-forming reaction, the molar concentration of Ginkgolide Bin the organic solvent may be a molar concentration conventional in theart for this type of reaction, the molar concentration in the presentdisclosure is particularly preferably 0.001 to 1 mol/L, furtherpreferably 0.001 to 0.5 mol/L, further more preferably 0.001 to 0.1mol/L (e.g., 0.025 mol/L, 0.024 mol/L, 0.023 mol/L).

In the ether-forming reaction, the molar ratio of Ginkgolide B to thecompound represented by formula 3 may be a molar ratio conventional inthe art for this type of reaction, the molar ratio in the presentdisclosure is particularly preferably 1:1 to 1:5, and further preferably1:1 to 1:3 (e.g., 1:2).

In the ether-forming reaction, the molar ratio of Ginkgolide B to thebase may be a molar ratio conventional in the art for this type ofreaction, the molar ratio in the present disclosure is particularlypreferably 1:1 to 1:10, and further preferably 1:3 to 1:6 (e.g., 1:4.6,1:4.4).

In the ether-forming reaction, the molar ratio of Ginkgolide B to thecatalyst may be a molar ratio conventional in the art for this type ofreaction, the molar ratio in the present disclosure is particularlypreferably 1:1 to 1:5, and further preferably 1:1 to 1:3 (e.g., 1:2).

In the ether-forming reaction, the reaction process may be monitored byconventional monitoring methods in the art (e.g., TLC, HPLC, or NMR),generally, when substantial disappearance of Ginkgolide B is monitored,the reaction reaches its endpoint. The reaction time of the presentdisclosure is particularly preferably 1 to 5 hours, further preferably 1to 3 hours (e.g., 2 hours).

The reaction temperature of the ether-forming reaction may be thereaction temperature conventional in the art for this type of reaction,the reaction temperature in the present disclosure is particularlypreferably the temperature at which the organic solvent used is refluxedat normal temperature and atmospheric pressure.

In a preferred embodiment of the present disclosure, the ether-formingreaction comprises the following steps: the Ginkgolide B is mixed withthe organic solvent, the compound represented by formula 3, the catalystand the base are sequentially added, and the reaction of the catalystand the base is carried out.

In a preferred embodiment of the present disclosure, the ether-formingreaction may further comprise a post-treatment step after the reactionis completed. The post-treatment steps may be a post-treatment stepconventional in the art for this type of reaction, preferablyfiltration, concentration and purification. The purification method maybe a conventional purification method in the art (e.g., columnchromatography).

The present disclosure also provides a method for preparing a compoundrepresented by formula 2, comprising the following steps:

In an organic solvent, under the action of an acid or a base, thecompound represented by formula 1 is subjected to hydrolysis reaction asshown below to obtain a compound represented by formula 1 in which R ishydrogen; all kinds of salts represented by formula 2 may be obtained bysalt-forming reaction between the compound and various bases.

wherein, L and cation are as defined above;

R is substituted or unsubstituted C₁₋₈ hydrocarbonyl, and the“substituted or unsubstituted C₁₋₈ hydrocarbonyl” is as described above.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the organic solvent may be an organic solvent conventional in the artfor this kind of reaction, the organic solvent of the present disclosureis particularly preferably alcohol solvent, and further preferablyanhydrous alcohol solvent. The alcohol solvent is preferably one or moreof methanol, ethanol, isopropanol and tert-butanol, and more preferablymethanol. The organic solvent is preferably anhydrous methanol.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the base may be a base conventional in the art for this kind ofreaction, such as inorganic base and/or organic base. The inorganic baseis preferably one or more of hydroxide, carbonate and bicarbonate. Thehydroxide is preferably one or more of lithium hydroxide, sodiumhydroxide and potassium hydroxide. The carbonate is preferably one ormore of sodium carbonate, potassium carbonate and cesium carbonate. Thebicarbonate is preferably one or more of sodium bicarbonate, potassiumbicarbonate and lithium bicarbonate. The organic base is preferablyamine organic base and/or imine organic base, and more preferably one ormore of triethylamine, pyridine, pyrrolidine and piperazine.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the molar ratio of the compound represented by formula 1 to the base maybe a molar ratio conventional in the art for this type of reaction, themolar ratio in the present disclosure is particularly preferably 1:1 to1:10, and further preferably 1:2 to 1:4 (e.g., 1:2.08, 1:2.78, 1:3.53).

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the reaction temperature of the hydrolysis reaction may be the reactiontemperature conventional in the art for this type of reaction, thereaction temperature in the present disclosure is particularlypreferably the temperature at which the organic solvent used is refluxedat normal temperature and atmospheric pressure.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the reaction process may be monitored by conventional monitoring methodsin the art (e.g., TLC, HPLC, or NMR), generally, when substantialdisappearance of the compound represented by formula 1 is monitored, thereaction reaches its endpoint. The reaction time of the presentdisclosure is particularly preferably 1 to 5 hours, further preferably 3to 4 hours (e.g., 3 hours).

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the molar concentration of the compound represented by formula 1 in theorganic solvent may be a molar concentration conventional in the art forthis type of reaction, the molar concentration in the present disclosureis particularly preferably 0.001 to 1 mol/L, further preferably 0.001 to0.5 mol/L, and further preferably 0.0034 to 0.16 mol/L (e.g., 0.034mol/L, 0.06 mol/L, 0.16 mol/L).

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the organic solvent may be an organic solvent conventional in the artfor this type of reaction, the organic solvent of the present disclosureis particularly preferably halogenated hydrocarbon solvent, furtherpreferably one or more of dichloromethane, chloroform and carbontetrachloride, and most preferably chloroform.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the acid may be an acid conventional in the art for this kind ofreaction, such as inorganic acid and/or organic acid. The inorganic acidis preferably one or more of hydrochloric acid, phosphoric acid,sulfuric acid and nitric acid. The organic acid is preferably one ormore of trifluoroacetic acid, p-sulfonic acid and methanesulfonic acid.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the molar ratio of the compound represented by formula 1 to the acid maybe a molar ratio conventional in the art for this type of reaction, themolar ratio in the present disclosure is particularly preferably 1:2 to1:100, and further preferably 1:50 to 1:70 (e.g., 1:61.5).

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the molar concentration of the compound represented by formula 1 in theorganic solvent may be a molar concentration conventional in the art forthis type of reaction, the molar concentration in the present disclosureis particularly preferably further preferably 0.001 to 1 mol/L, andfurther preferably 0.001 to 0.5 mol/L (e.g., 0.219 mol/L).

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the reaction temperature of the hydrolysis reaction may be the reactiontemperature conventional in the art for this type of reaction, thereaction temperature in the present disclosure is particularlypreferably 15 to 25° C.

In the hydrolysis reaction, when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the reaction process may be monitored by conventional monitoring methodsin the art (e.g., TLC, HPLC, or NMR), generally, when substantialdisappearance of the compound represented by formula 1 is monitored, thereaction reaches its endpoint. The reaction time of the presentdisclosure is particularly preferably 1 to 5 hours, further preferably 1to 4 hours (e.g., 2 hours).

In a preferred embodiment of the present disclosure, the hydrolysisreaction comprises the following steps: mixing the compound representedby formula 1 with the organic solvent, and adding the acid or base forreaction.

In a preferred embodiment of the present disclosure, the hydrolysisreaction may further comprise a post-treatment step after the reactionis completed, and the post-treatment step may be a post-treatment stepconventional in the art. When the compound represented by formula 1 issubjected to the hydrolysis reaction under the action of the acid, thepost-treatment step is preferably concentration. When the compoundrepresented by formula 1 is subjected to the hydrolysis reaction underthe action of the base, the post-treatment step is preferably pHadjustment of the reaction mixture to 3-4 at the end of the reaction,concentration and filtration. The reagent used for pH adjustment may bean acid conventional in the art, the reagent of the present disclosureis particularly preferably dilute hydrochloric acid.

The present disclosure also provides a preparation method of thecompound represented by formula 2, comprising the following steps: in anorganic solvent, the compound represented by formula 1 (R is hydrogen)is mixed with a base for salt-forming reaction.

In the salt-forming reaction, the organic solvent may be an organicsolvent conventional in the art for this kind of reaction, the organicsolvent of the present disclosure is particularly preferably alcoholsolvent, and further preferably a mixed solvent of ethanol and methanol.

In the salt-forming reaction, the molar concentration of the compoundrepresented by formula 1(R is hydrogen) in the organic solvent may be amolar concentration conventional in the art for this kind of reaction,the molar concentration of the present disclosure is particularlypreferably 0.01 to 0.1 mol/L, and further preferably 0.06 to 0.07 mol/L(e.g., 0.068 mol/L).

In the salt-forming reaction, the inorganic base is as described above.

In the salt-forming reaction, the organic base is as described above.

In the salt forming reaction, the molar ratio of the compoundrepresented by formula 1(R is hydrogen) to the base may be a molar ratioconventional in the art for this kind of reaction, the molar ratio ofthe present disclosure is particularly preferably 1:1 to 3.

The reaction temperature of the salt-forming reaction may be a reactiontemperature conventional in the art for this kind of reaction, thereaction temperature of the present disclosure is particularlypreferably to be 15 to 40° C.

In the salt-forming reaction, the reaction process may be monitored byconventional monitoring methods in the art (e.g., TLC, HPLC, or NMR),generally, when substantial disappearance of the compound represented byformula 1(R is hydrogen) is monitored, the reaction reaches itsendpoint. The reaction time of the present disclosure is particularlypreferably 1 to 4 hours, further preferably 1 to 2 hours (e.g., 1, 2hours).

In a preferred embodiment of the present disclosure, the salt-formingreaction comprises the following steps: mixing the compound representedby formula 1 (R is hydrogen) with the organic solvent, adding theorganic solvent dissolved with a base for reaction.

In a preferred embodiment of the present disclosure, the salt-formingreaction may further comprise a post-treatment step after the reactionis completed, and the post-treatment step may be a post-treatment stepconventional in the art. In the present disclosure, the post-treatmentstep is particularly preferably recrystallization or directconcentration. The solvent used for recrystallization may be an organicsolvent conventional in the art (e.g., diethyl ether).

The present disclosure also provides a pharmaceutical compositioncomprising a therapeutically effective dose of the compound representedby formula 1 or the pharmaceutically acceptable salt thereof asdescribed above, or the pharmaceutically acceptable salt of the compoundrepresented by formula 2 as described above.

The present disclosure also provides a use of the compound representedby formula 1 or the pharmaceutically acceptable salt thereof asdescribed above, or the pharmaceutically acceptable salt of the compoundrepresented by formula 2 as described above, or the pharmaceuticalcomposition as described above in the preparation of medicaments for theprevention and treatment of diseases related to platelet activatingfactor such as ischemic stroke, thrombosis, angina pectoris,cardiopulmonary infarction, and inflammation or asthma.

The present disclosure also provides a method for the prevention andtreatment of diseases related to platelet activating factor such asischemic stroke, thrombosis, angina pectoris, cardiopulmonaryinfarction, and inflammation or asthma, comprising administering atherapeutically effective amount of the compound represented by formula1 or the pharmaceutically acceptable salt of the compound represented byformula 2 or the pharmaceutical composition as described above to asubject.

The term “pharmaceutically acceptable salt” refers to the salt of thecompound of the present disclosure, which is prepared from the compoundwith specific substituent discovered by the present disclosure and arelatively nontoxic base. The compounds of the present disclosureinclude relatively acidic functional groups, and base addition salts maybe obtained by contacting the neutral form of such compounds with asufficient amount of base in a pure solution or a suitable inertsolvent. Pharmaceutically acceptable base addition salts include sodium,potassium, calcium, magnesium, zinc, ammonium, various organic ammonia,or various amino acid salts or similar salts.

The term “therapeutically effective dose” refers to a sufficient amountof a medication or medicament that is nontoxic but may achieve thedesired effect. The determination of effective dose varies from personto person, and depends on the age and general condition of the subject,and also depends on the specific active substance, the appropriateeffective dose in a case may be determined by the person skilled in theart according to routine tests.

The term “subject” refers to any animal that will or has receivedadministration of the compound or the pharmaceutical compositionaccording to the embodiment of the present disclosure, the subject ispreferably mammals, more preferably humans. The term “mammal” includesany mammal. Examples of mammals include, but are not limited to, cattle,horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs,monkeys, humans, etc., and most preferably humans.

In the present disclosure, room temperature refers to 15 to 25° C.Normal temperature refers to 25° C. Atmospheric pressure refers to oneatmosphere, 101 KPa. Overnight refers to 12 to 18 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1, test results of anti-platelet aggregation activity in vitro ofembodiment 1-21 (n=5, 1 μM),

Results: The compounds of the embodiments show obvious inhibitory effecton platelet aggregation, with blank as the standard 1, the plateletaggregation rate of Ginkgolide B at 1 μM concentration is 63.42%, andthe platelet aggregation rate under the action of the compounds of eachembodiment is lower than that of Ginkgolide B.

FIG. 2, evaluation results of embodiments 2, 7, 10, 12, 13, 14, 17 and21 inhibiting platelet aggregation activity in SD rats (n=10, 50 mg/kg),

Results: The embodiments show obvious anti-aggregation activity onplatelet aggregation in SD rats, the activities of the compounds of theembodiments are higher than that of Ginkgolide B except for embodiment10, and the in vivo activities of embodiments 12, 13 and 14 areparticularly significant (P<0.001), which could be applied to clinicalanticoagulation and treatment of related diseases.

FIG. 3, evaluation results of the activity of embodiments 2, 7, 10, 12,13, 14, 17 and 21 for reducing the area ratio of hemicerebral infarctionin SD rats (n=10, 50 mg/kg),

Results: Compared with the model group, the compounds of each embodimentcan obviously reduce the area ratio of hemicerebral infarction in rats,the activities of the compounds in the embodiments are smaller than thatof Ginkgolide B group except for embodiment 10, and the activities ofembodiments 12, 13 and 14 are particularly significant (P<0.001), whichcan be used for clinical treatment of cerebral ischemia and cerebralischemia related diseases.

FIG. 4, partial slice photos of blank model group, Ginkgolide B,embodiment 10, and embodiment 12 group (original pictures are in color),

Results: Embodiment 12 is significantly better than Ginkgolide B andembodiment 10, can significantly reduce the area ratio of hemicerebralinfarction of acute cerebral ischemia in SD rats, and can be used forclinical anti-coagulation and anti-cerebral ischemia, and the treatmentof related diseases.

DETAILED DESCRIPTION OF THE EMBODIMENT Embodiment 1 Preparation of10-O-(methoxyformylmethyl) Ginkgolide B

mg (0.5 mmol) of Ginkgolide B was dissolved in 20 mL of THF, 190 mg (2.0mmol) of methyl chloroacetate, 166 mg (1.0 mmol) of KI and 310 mg (2.3mmol) of potassium carbonate were added in turn, the mixture was heated,refluxed and stirred for 2 hours, and the plate layer was tracked untilthe substrate substantially disappeared, the post-treatment was carriedout after the completion of the reaction, potassium carbonate wasremoved by filtration, the mother liquor was concentrated and theresidue was separated by column chromatography to obtain a light yellowsolid; then the residue was filtered and dried to obtain 121 mg of theproduct with a yield of 48%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H,t-Bu), 1.09 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87 (ddd, 1H, 7α-H),2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.71 (s, 1H, —OCH₃), 4.06 (m,1H, 1-H), 4.42 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d, 1H, 2-H), 4.80 (d,1H, J=16 Hz, 10-CH₂—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H, 10-H), 5.33 (d,1H, 6-H), 6.19 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 497 (M+H⁺)

Embodiment 2 Preparation of 10-O-(methoxyformylallyl) Ginkgolide B

300 mg (0.71 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 251 mg(1.4 mmol) of methyl 4-bromo-2-butenoate, 232 mg (1.4 mmol) of KI and434 mg (3.1 mmol) of potassium carbonate were added in turn, the mixturewas heated, refluxed and stirred for 2 hours, and the plate layer wastracked until the substrate substantially disappeared, thepost-treatment was carried out after the completion of the reaction,potassium carbonate was removed by filtration, the mother liquor wasconcentrated and the residue was separated by column chromatography toobtain a light yellow solid, then the residue was filtered and dried toobtain 192 mg of the product with a yield of 52.5%. ¹H-NMR (DMSO-d₆, 400MHz): 1.01 (s, 9H, t-Bu), 1.08 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87(ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.73 (s, 1H,—OCH₃), 4.06 (m, 1H, 1-H), 4.42 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d, 1H,2-H), 4.80 (d, 1H, J=16 Hz, 10-CH₂—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H,10-H), 5.33 (d, 1H, 6-H), 5.65 (m, 1H, —CH═), 5.76 (m, 1H, —CH═), 6.19(s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 523 (M+H⁺)

Embodiment 3 Preparation of 10-O-(tert-butoxyformylmethyl) Ginkgolide B

300 mg (0.70 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 276 mg(1.41 mmol) of tert-butyl bromoacetate, 235 mg (1.41 mmol) of KI and 434mg (3.2 mmol) of potassium carbonate were added in turn, the mixture washeated, refluxed and stirred for 2 hours, and the plate layer wastracked until the substrate substantially disappeared, thepost-treatment was carried out after the completion of the reaction,potassium carbonate was removed by filtration, the mother liquor wasconcentrated and the residue was separated by column chromatography toobtain light yellow needle-like crystals; then the residue was filteredand dried to obtain 220 mg of the product with a yield of 58%. ¹H-NMR(DMSO-d₆, 400 MHz): 0.99 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.42 (s,9H, —O-t-Bu), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.79 (q, 1H, 14-H), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz,10-CH₂—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH₂—), 5.13 (d,1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H),6.50 (s, 1H, 3-OH). MS (m/z): 539 (M+H⁺)

Embodiment 4 Preparation of 10-O-(methoxyformylmethoxyethyl) GinkgolideB

300 mg (0.70 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 345 mg(1.41 mmol) of methyl iodoethoxyacetate, 235 mg (1.41 mmol) of KI and434 mg (3.2 mmol) of potassium carbonate were added in turn, the mixturewas heated, refluxed and stirred for 2 hours, and the plate layer wastracked until the substrate substantially disappeared, thepost-treatment was carried out after the completion of the reaction,potassium carbonate was removed by filtration, the mother liquor wasconcentrated and the residue was separated by column chromatography toobtain light yellow needle-like crystals; then the residue was filteredand dried to obtain 219 mg of the product with a yield of 58%. ¹H-NMR(DMSO-d₆, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd,1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H),3.57 (m, 4H, —OCH₂CH₂O—), 3.92 (s, 3H, —OCH₃), 4.05 (m, 1H, 1-H), 4.28(d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d, 11H, 2-H), 4.65 (d, 1H, J=16 Hz,10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H),6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 541 (M+H⁺)

Embodiment 5 Preparation of 10-O-(methoxyformylmethoxyethoxyethyl)Ginkgolide B

300 mg (0.70 mmol) of GinkgolideB was dissolved in 30 mL of THF, 360 mg(1.49 mmol) of methyl bromoethoxyacetate, 235 mg (1.41 mmol) of KI and434 mg (3.2 mmol) of potassium carbonate were added in turn, the mixturewas heated, refluxed and stirred for 2 hours, and the plate layer wastracked until the substrate substantially disappeared, thepost-treatment was carried out after the completion of the reaction,potassium carbonate was removed by filtration, the mother liquor wasconcentrated and the residue was separated by column chromatography toobtain light yellow needle-like crystals; then the residue was filteredand dried to obtain 231 mg of the product with a yield of 56%. ¹H-NMR(DMSO-d₆, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd,1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H),3.52-3.59 (m, 8H, —OCH₂CH₂O—), 3.92 (s, 3H, —OCH₃), 4.05 (m, 1H, 1-H),4.28 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz,10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H),6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 585 (M−H⁺)

Embodiment 6 Preparation of 4-(Ginkgolide B-10-oxy)-2-butenoic Acid

500 mg (0.96 mmol) of the product of embodiment 2 was dissolved in 6 mLof anhydrous methanol, 51 mg (2.0 mmol) of lithium hydroxide was addedthereto, the mixture was heated, refluxed and stirred, the plate layerwas tracked until the substrate substantially disappeared, the reactionwas completed after 3 hours, the pH value was adjusted to about 4-5 withdilute hydrochloric acid, part of methanol was evaporated, the mixturewas placed allowing solid to precipitate, then filtered to obtain 393 mgof the product with a yield of 80.6%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.01(s, 9H, t-Bu), 1.08 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87 (ddd, 1H,7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 4.06 (m, 1H, 1-H), 4.42(d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d, 1H, 2-H), 4.80 (d, 1H, J=16 Hz,10-CH₂—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H, 10-H), 5.33 (d, 1H, 6-H),5.65 (m, 1H, —CH═), 5.76 (m, 1H, —CH═), 6.19 (s, 1H, 12-H), 6.48 (s, 1H,3-OH), 13.67 (s, 1H, —COOH). MS (m/z): 507 (M−H⁺)

Embodiment 7 Preparation of 2-(Ginkgolide B-10-oxy)acetic Acid

1.18 g (2.19 mmol) of the product of embodiment 3 was dissolved in 10 mLof chloroform, and 10 mL of trifluoroacetic acid was added, and stirredat room temperature, the plate layer was tracked until the substratesubstantially disappeared. After 2 hours, the post-treatment of thereaction was finished, and the solvent was evaporated under reducedpressure to obtain a light yellow solid, then the residue was filteredand dried to obtain 1.05 g of the product with a yield of 99%. ¹H-NMR(DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd,1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H),4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH₂—), 4.62 (d, 1H, 2-H),4.71 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H),5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 13.70 (s,1H, —COOH). MS (m/z): 481 (M−H⁺)

Embodiment 8 Preparation of 2-(Ginkgolide B-10-oxyethoxy)acetic Acid

200 mg (0.37 mmol) of the product of embodiment 4 was dissolved in 6 mLof anhydrous methanol, 25 mg (1.0 mmol) of lithium hydroxide was addedthereto. Then the mixture was heated, refluxed and stirred, the platelayer was tracked until the substrate substantially disappeared, thereaction was completed after 3-4 hours. The pH was adjusted to about 4-5with dilute hydrochloric acid, part of methanol was evaporated, themixture was placed allowing solid to precipitate, then filtered toobtain 174 mg of the product with a yield of 91.9%. ¹H-NMR (DMSO-d₆, 400MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86(ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H,—OCH₂CH₂O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d,1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25 (s,1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH),12.8 (s, 1H, —COOH). MS (m/z): 525 (M−H⁺)

Embodiment 9 Preparation of 2-(Ginkgolide B-10-oxyethoxyethoxy)aceticAcid

100 mg (0.17 mmol) of the product of embodiment 5 was dissolved in 5 mLof anhydrous methanol, 15 mg (0.6 mmol) of lithium hydroxide was addedthereto, the mixture was heated, refluxed and stirred, the plate layerwas tracked until the substrate substantially disappeared, the reactionwas completed after 3-4 hours. The pH value was adjusted to about 4-5with dilute hydrochloric acid, part of methanol was evaporated, themixture was placed allowing solid to precipitate, then filtered toobtain 82 mg of the product with a yield of 84.6%. ¹H-NMR (DMSO-d₆, 400MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86(ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.54-3.64 (m,8H, —OCH₂CH₂O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH₂—), 4.63(d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25(s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H,3-OH), 13.5 (s, 1H, —COOH). MS (m/z): 569 (M−H⁺)

Embodiment 10 Preparation of 2-(Ginkgolide B-10-oxy)sodium Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 2 times the molar amount ofNa₂CO₃ in methanol solution was added dropwise, the mixture was stirredat room temperature for 1 hour, an equal volume of absolute ether wasadded, the mixture was placed overnight allowing solid to precipitate toobtain 185 mg of the product, with a yield of 89.5%. ¹H-NMR (DMSO-d₆,400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H),1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d,1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d,1H, J=16 Hz, 10-CH₂—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s,1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 481 (M−H⁺,neg.).

Embodiment 11 Preparation of 2-(Ginkgolide B-10-oxy)ammonium Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 2 times the molar amount ofammonia in methanol solution was added dropwise, and the mixture wasstirred at room temperature for 2 hours, then the solvent was evaporatedunder reduced pressure, 10 mL of ether was added for washing, and thenthe mixture was filtered to obtain 197 mg of light yellow solid with ayield of 96.3%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d,3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 8.10 (br-s, 4H, NH). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 12 Preparation of 2-(Ginkgolide B-10-oxy)lysine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, equal molar amount of lysinein methanol solution was added dropwise, and the mixture was stirred atroom temperature for 2 hours, then the solvent was evaporated underreduced pressure, 10 mL of ether was added for washing, and then themixture was filtered to obtain 255 mg of light yellow solid with a yieldof 98.1%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H,14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H),2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH₂—),4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s, 1H, 10-H),5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H,3-OH), 1.25 (m, 2H, CH₂), 1.78 (m, 2H, CH₂), 2.03 (m, 2H, CH₂), 3.33 (m,2H, CH₂), 3.48 (m, 1H, CH), 6.82 (br-s, 6H, NH). MS (m/z): 481 (M−H⁺,neg.).

Embodiment 13 Preparation of 2-(Ginkgolide B-10-oxy)arginine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount ofarginine in methanol solution was added dropwise, and the mixture wasstirred at room temperature for 2 hours, then the solvent was evaporatedunder reduced pressure, 10 mL of ether was added for washing, and thenthe mixture was filtered to obtain 243 mg of light yellow solid with ayield of 92.5%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d,3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 1.28 (m, 2H, CH₂), 1.35 (m, 2H, CH₂), 1.82 (m, 2H,CH₂), 3.49 (m, 1H, CH), 6.32-7.01 (br-s, 7H, N—H). MS (m/z): 481 (M−H⁺,neg.).

Embodiment 14 Preparation of 2-(Ginkgolide B-10-oxy)histidine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 1.8 times the molar amount ofhistidine in methanol solution was added dropwise, and the mixture wasstirred at room temperature for 2 hours, then the solvent was evaporatedunder reduced pressure, 10 mL of ether was added for washing, and thenthe mixture was filtered to obtain 259 mg of light yellow solid with ayield of 99.1%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d,3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 2.90-3.16 (m, 2H, CH₂), 4.49 (m, 1H, CH), 7.72 (s,1H, CH), 8.91 (s, 1H, CH), 6.30-7.01 (br-s, 3H, N—H), 10.25 (br-s, 2H,N—H). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 15 Preparation of 2-(Ginkgolide B-10-oxy)triethylamineAcetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 2 times the molar amount oftriethylamine in methanol solution was added dropwise, and the mixturewas stirred at room temperature for 2 hours, then the solvent wasevaporated under reduced pressure, 10 mL of ether was added for washing,and then the mixture was filtered to obtain 184 mg of light yellow solidwith a yield of 76.9%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu),1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd,1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 1.03 (t, 9H, CH₃—CH₂), 3.05 (q, 6H, CH₃—CH₂), 9.25(br-s, 1H, N—H). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 16 Preparation of 2-(Ginkgolide B-10-oxy)diethylamine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, equal molar amount ofdiethylamine in methanol solution was added dropwise, and the mixturewas stirred at room temperature for 2 hours, then the solvent wasevaporated under reduced pressure, 10 mL of ether was added for washing,and then the mixture was filtered to obtain 178 mg of light yellow solidwith a yield of 78.2%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu),1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd,1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 1.05 (t, 6H, CH₃—CH₂), 3.07 (q, 4H, CH₃—CH₂), 8.27(br-s, 2H, N—H). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 17 Preparation of 2-(Ginkgolide B-10-oxy) n-pentylamineAcetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 3 times the molar amount ofn-pentylamine in methanol solution was added dropwise, and the mixturewas stirred at room temperature for 2 hours, then the solvent wasevaporated under reduced pressure, 10 mL of ether was added for washing,and then the mixture was filtered to obtain 193 mg of light yellow solidwith a yield of 82.7%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu),1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd,1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 1.05 (m, 3H, CH₃—CH₂), 1.25-1.30 (m, 4H, —CH₂—CH₂),2.05 (m, 2H, —CH₂), 3.37 (m, 2H, —CH₂), 7.27-7.55 (br-s, 3H, N—H). MS(m/z): 481 (M−H⁺, neg.).

Embodiment 18 Preparation of 2-(Ginkgolide B-10-oxy) pyrrolidine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount ofpyrrolidine in methanol solution was added dropwise, and the mixture wasstirred at room temperature for 2 hours, then the solvent was evaporatedunder reduced pressure, 10 mL of ether was added for washing, and thenthe mixture was filtered to obtain 183 mg of light yellow solid with ayield of 80.7%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d,3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 2.02 (m, 4H, —CH₂), 3.17 (m, 4H, —CH₂), 7.27-7.55(br-s, 2H, N—H). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 19 Preparation of 2-(Ginkgolide B-10-oxy)morpholine Acetate

200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7)was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount ofmorpholine in methanol solution was added dropwise, and the mixture wasstirred at room temperature for 2 hours, then the solvent was evaporatedunder reduced pressure, 10 mL of ether was added for washing, and thenthe mixture was filtered to obtain 202 mg of light yellow solid with ayield of 86.6%. ¹H-NMR (DMSO-d₆, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d,3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H,7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz,10-CH₂—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH₂—), 5.28 (s,1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H),6.48 (s, 1H, 3-OH), 3.52 (m, 4H, —CH₂), 4.20 (m, 4H, —CH₂), 7.28-7.35(br-s, 2H, N—H). MS (m/z): 481 (M−H⁺, neg.).

Embodiment 20 Preparation of 2-(Ginkgolide B-10-oxyethoxy)sodium Acetate

250 mg (0.48 mmol) of 2-(Ginkgolide B-10-oxyethoxy) acetic acid(embodiment 8) was dissolved in 5 mL of absolute ethanol, 1.2 times themolar amount of sodium carbonate in methanol solution was addeddropwise, and the mixture was stirred at room temperature for 2 hours,then the solvent was evaporated under reduced pressure, 10 mL of etherwas added for washing, and then the mixture was filtered to obtain 208mg of light yellow with a yield of 79.1%. ¹H-NMR (DMSO-d₆, 400 MHz):0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd,1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H,—OCH₂CH₂O—), 4.05 (m, 1H, 1-H), 4.30 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d,1H, 2-H), 4.63 (d, 1H, J=16 Hz, 10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25 (s,1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS(m/z): 525 (M−H⁺, Neg.)

Embodiment 21 Preparation of 2-(GinkgolideB-10-oxyethoxy)N-methyl-D-glucosamine Acetate

mg (0.48 mmol) of 2-(Ginkgolide B-10-oxyethoxy) acetic acid (embodiment8) was dissolved in 5 mL of absolute ethanol, 1.5 times the molar amountof N-methyl-D-glucosamine in methanol solution was added dropwise, andthe mixture was stirred at room temperature for 2 hours, then thesolvent was evaporated under reduced pressure, 20 mL of ether was addedfor washing, and then the mixture was filtered to obtain 245 mg of lightyellow solid with a yield of 70.8%. ¹H-NMR (DMSO-d₆, 400 MHz): 0.98 (s,9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H,7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H,—OCH₂CH₂O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH₂—), 4.63 (d,1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH₂—), 5.13 (d, 1H, 1-OH), 5.25 (s,1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH),2.85 (s, 3H, CH₃), 3.35-3.39 (m, 9H, CH, OH), 3.58-3.62 (m, 4H,CH_(2*2)), 8.89 (br-s, 2H, NH). MS (m/z): 525 (M−H⁺)

Embodiment 22 In Vitro Anti-Platelet Aggregation Activity EvaluationExperiment

Experimental method: New Zealand white rabbits were anesthetized withsodium pentobarbital (2%, 2 mL/kg), about 40 mL of blood was obtained byabdominal aortic puncture, and the supernatant was collected asplatelet-rich serum (PRP) after centrifugation at 1000 rpm/min for 10min, the remaining blood was centrifuged at 4000 rpm/min for 10 min, andthe supernatant was collected as platelet-poor serum (PPP); blankcontrol group: 100 μL PRP+100 μL normal saline; drug group: 100 μLPRP+100 μL 0.05% DMSO dissolved drug (Ginkgolide B was positive controlgroup), and the final drug concentration was 1 μM. After incubation for5 min, 2 μL PAF(10× final concentration was 145 nm) was added; theplatelet aggregation rate was measured by a platelet aggregationinstrument, and each sample was repeated for five groups, the obtainedaggregation rates were divided by the average value of the blank controlgroup to obtain corrected values for comparison.

The results showed that the compounds of each embodiment exhibitedobvious inhibitory effect on platelet aggregation, with blank as thestandard 1, the platelet aggregation rate of Ginkgolide B at 1 μMconcentration was 63.42%, and the platelet aggregation rate of thecompounds of each embodiment was lower than that of Ginkgolide B, thespecific data are shown in Table 1 and FIG. 1. Embodiments 2, 7, 12, 13,14, 17 and 21 are compounds with significant activity.

TABLE 1 Test results of anti-platelet aggregation activity in vitro ofEmbodiment 1-21 Platelet Compound aggregation rate number (%, 1 μM)blank 100 Embodiment 1 29.98 Embodiment 2 10.30 Embodiment 3 26.10Embodiment 4 46.70 Embodiment 5 39.34 Embodiment 6 45.67 Embodiment 717.66 Embodiment 8 23.68 Embodiment 9 34.99 Embodiment 10 39.34Embodiment 11 56.53 Embodiment 12 12.23 Embodiment 13 15.66 Embodiment14 19.74 Embodiment 15 24.65 Embodiment 16 28.87 Embodiment 17 21.90Embodiment 18 26.45 Embodiment 19 35.77 Embodiment 20 45.32 Embodiment21 18.64 Ginkgolide B 63.42

Embodiment 23 Evaluation Experiment of Anticoagulant Activity in SD Rats

Experimental method: Rats were randomly divided into 10 rats in eachgroup, and each group was given the corresponding test drug (50 mg/kg)by gavage after weighing, once a day for 3 days. One hour after the lastadministration, the rats were anesthetized, 8 mL of blood was taken fromfemoral artery, and the whole blood was anticoagulated with 3.8% sodiumcitrate, the whole blood anticoagulated with sodium citrate (3.8%trisodium citrate:whole blood=1:9) was centrifuged for 10 min at 800r/min, and the upper plasma obtained at this speed was platelet-richplasma (PRP), after PRP was sucked out, the remaining blood wascentrifuged at 3000 r/min for 10 min, the plasma obtained at this speedwas platelet poor plasma (PPP).

150 μL of PRP in each group was sucked and added to the 96-well plate(adjusted to zero by PPP), and ADP inducer was added, the absorbancevalue A1 was measured at the wavelength of 650 nm in the microplatereader, which was the absorbance value of each group at 0 min; theoscillation mode of the microplate reader was turned on, and theabsorbance value A2 was detected again after 5 min, which was theabsorbance value of each group at 5 min. Since the addition of ADP wouldcause platelet aggregation and change the light permeability, themaximum platelet aggregation rate (PAGM) within 5 min was measuredaccording to this principle.

Maximum platelet aggregation rate (PAGM)=(A1−A2)/A1×100

The results are shown in table 2 and FIG. 2: all the embodiments exhibitobvious anti-aggregation activity on platelet aggregation in SD rats,the activities of the embodiments were higher than those of Ginkgolide Bexcept for embodiment 10. The in vivo activities of embodiments 12, 13and 14 were particularly significant, which could be applied to clinicalanticoagulation and treatment of related diseases.

TABLE 2 Test results of anti-platelet aggregation activity in vitro ofEmbodiment 2, 7, 10, 12, 13, 14, 17 and 21 (n = 10). Average maximumplatelet Standard No. aggregation rate (%) deviation (SD, %) Solventgroup 51.45 12.10 Ginkgolide B 39.57 11.41 Embodiment 2 32.60  9.50Embodiment 7 35.20  7.50 Embodiment 10 42.20  9.52 Embodiment 12 22.65 8.65 Embodiment 13 21.25  7.65 Embodiment 14 26.82  9.47 Embodiment 1734.20  8.60 Embodiment 21 29.35  7.79

Embodiment 24 Evaluation Experiment of Anti-Acute Cerebral IschemiaActivity

Methods: SD rats were weighed and randomly divided into 10 rats in eachgroup, and were anesthetized by intraperitoneal injection of 15% chloralhydrate 300 mg/kg, their left lateral position was fixed on the ratoperating table, and the left temporal top and face were shaved anddisinfected with 75% ethanol, the skin was cut between the left eye andleft ear, the temporal muscle and masseter muscle were passivelyseparated, and the wing plate of the temporal bone was exposed, underthe operating microscope, a 2 mm×2 mm bone window was ground with acranial drill 1 mm from the union of the temporal bone and the temporalscalene near the mouth, and the skull was pried open with a pry bar. Atthis time, a relatively straight blood vessel with few branches can beseen through the dura mater, that is, the middle cerebral artery.Bipolar electrocoagulation forceps were used to cauterize the olfactorytract from 1 mm to the inferior cerebral vein, which completely blockedthe blood flow. The temporal muscle and skin were sutured in turn, andthen the rat was administered by gavage (50 mg/kg). After the rats wereawakened, they were put back into their cages and continued to be rearedfor 24 h.

The rats were anesthetized by intraperitoneal injection of 15% chloralhydrate 300 mg/kg again, the brains were decapitated, the olfactorybulb, cerebellum and brain stem were removed, quick-frozen in therefrigerator at −20° C. for about 15 min, and then the frozen brainswere cut into 7 slices. The brain slices were stained in 1% TTC dyesolution (incubated at 37° C. in the dark for about 5-10 min), theinfarcted area of brain slices after staining was white, while thenon-infarcted area was rose red; after staining was completed, the brainslices were moved to 10% formaldehyde solution and kept away from lightfor 24 hours, finally, a digital camera was used to take pictures, theareas of frontal and reverse infarcted areas and non-infarcted areaswere measured by image analysis software (ImageJ, version: 1.4.3.67),and the ratio of infarcted areas in the total infarcted cerebralhemisphere was calculated.

The experimental results are shown in table 3 and FIG. 3: compared withthe model group, the compounds of each embodiment can obviously reducethe ratio of hemispheric infarction area in rats. The hemisphericinfarction area of each group was smaller than that of Ginkgolide Bgroup except for embodiment 10, and the activities of embodiments 12, 13and 14 were particularly significant, which can be used for clinicaltreatment of cerebral ischemia and cerebral ischemia related diseases.

FIG. 3. evaluation results of the activity of embodiments 2, 7, 10, 12,13, 14 and 21 for reducing the hemicerebral infarction area ratio in SDrats(n=10)

Average area ratio of standard Compound hemicerebral infarction (%)deviation Model group 31.91 1.66 Ginkgolide B 26.12 6.04 Embodiment 221.56 4.35 Embodiment 7 25.14 4.56 Embodiment 10 29.61 3.00 Embodiment12 18.83 5.75 Embodiment 13 20.14 5.27 Embodiment 14 17.98 4.76Embodiment 17 25.31 5.13 Embodiment 21 22.66 3.67

Although the specific embodiments of the present disclosure have beendescribed above, those skilled in the art should understand that theseare only examples, various changes or modifications can be made to theseembodiments without departing from the principle and essence of thepresent invention. Therefore, the protection scope of the presentdisclosure is defined by the appended claims.

What is claimed is:
 1. A compound represented by formula 1 or apharmaceutically acceptable salt thereof, wherein:

L is heteroatom, substituted or unsubstituted C₁₋₁₀ hydrocarbonylene,substituted or unsubstituted C₁₋₁₀ heterohydrocarbonylene containingheteroatoms, or not existed, when L is heteroatom or L is substituted orunsubstituted C₁₋₁₀ heterohydrocarbonylene containing heteroatoms, theheteroatoms are selected from one or more of oxygen, nitrogen andsulfur; when there are multiple heteroatoms, the heteroatoms are thesame or different; R is hydrogen or substituted or unsubstituted C₁₋₈hydrocarbonyl; the substituent in the substituted C₁₋₁₀hydrocarbonylene, the substituted C₁₋₁₀ heterohydrocarbonylenecontaining heteroatoms and the substituted C₁₋₈ hydrocarbonyl isindependently one or more of halogen, hydroxyl, C₁₋₁₀ alkoxy, phenyl andC₁₋₁₀ alkyl, and when multiple substituents exist, the substituents arethe same or different; and the compound represented by the formula 1 isnot


2. The compound represented by formula 1 or the pharmaceuticallyacceptable salt thereof according to claim 1, wherein: the L isheteroatom, substituted or unsubstituted C₁₋₁₀ alkylene, substituted orunsubstituted C₂₋₁₀ alkenylene, substituted or unsubstituted C₂₋₁₀alkynylene, substituted or unsubstituted C₃₋₁₀ cycloalkylene,substituted or unsubstituted C₃₋₁₀ cycloalkenylene, substituted orunsubstituted C₄₋₁₀ cycloalkynylene, substituted or unsubstitutedphenylene, substituted or unsubstituted naphthylene, substituted orunsubstituted C₁₋₁₀ heteroalkylene, substituted or unsubstituted C₂₋₁₀heteroalkenylene, substituted or unsubstituted C₂₋₁₀ heteroalkynylene,substituted or unsubstituted C₂₋₁₀ heterocycloalkylene, substituted orunsubstituted C₂₋₁₀ heterocycloalkenylene, substituted or unsubstitutedC₂₋₁₀ heterocycloalkynylene, substituted or unsubstituted C₁₋₁₀heteroarylene, or not existed; or the R is hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl,substituted or unsubstituted C₄₋₈ cycloalkynyl, or substituted orunsubstituted phenyl; or when the substituent in the substituted C₁₋₁₀hydrocarbonylene, the substituted C₁₋₁₀ heterohydrocarbonylenecontaining heteroatoms and the substituted C₁₋₈ hydrocarbonyl ishalogen, the halogen is fluorine, chlorine, bromine or iodine; or whenthe substituent in the substituted C₁₋₁₀ hydrocarbonylene, thesubstituted C₁₋₁₀ heterohydrocarbonylene containing heteroatoms and thesubstituted C₁₋₈ hydrocarbonyl is C₁₋₁₀ alkoxy, the C₁₋₁₀ alkoxy is C₁₋₄alkoxy; or when the substituent in the substituted C₁₋₁₀hydrocarbonylene, the substituted C₁₋₁₀ heterohydrocarbonylenecontaining heteroatoms and the substituted C₁₋₈ hydrocarbonyl is C₁₋₁₀alkyl, the C₁₋₁₀ alkyl is C₁₋₄ alkyl.
 3. The compound represented byformula 1 or the pharmaceutically acceptable salt thereof according toclaim 1, wherein: the L is heteroatom, substituted or unsubstitutedC₃₋₁₀ alkylene, substituted or unsubstituted C₂₋₁₀ alkenylene,substituted or unsubstituted C₂₋₁₀ alkynylene, substituted orunsubstituted C₃₋₁₀ cycloalkylene, substituted or unsubstituted C₃₋₁₀cycloalkenylene, substituted or unsubstituted C₄₋₁₀ cycloalkynylene,substituted or unsubstituted phenylene, substituted or unsubstitutednaphthylene, substituted or unsubstituted C₁₋₁₀ heteroalkylene,substituted or unsubstituted C₂₋₁₀ heteroalkenylene, substituted orunsubstituted C₂₋₁₀ heteroalkynylene, substituted or unsubstituted C₂₋₁₀heterocycloalkylene, substituted or unsubstituted C₂₋₁₀heterocycloalkenylene, substituted or unsubstituted C₂₋₁₀heterocycloalkynylene, substituted or unsubstituted C₁₋₁₀ heteroarylene,or not existed; or the R is hydrogen, methyl, benzyl, substituted orunsubstituted C₃₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl,substituted or unsubstituted C₄₋₈ cycloalkynyl, or substituted orunsubstituted phenyl.
 4. The compound represented by formula 1 or thepharmaceutically acceptable salt thereof according to claim 1, wherein:when the L is heteroatom, the heteroatom is oxygen or sulfur; or whenthe L is substituted or unsubstituted C₃₋₁₀ alkylene, the C₃₋₁₀ alkylenein the substituted or unsubstituted C₃₋₁₀ alkylene is C₃₋₅ alkylene; orwhen the L is substituted or unsubstituted C₂₋₁₀ alkenylene, the C₂₋₁₀alkenylene in the substituted or unsubstituted C₂₋₁₀ alkenylene is C₃₋₆alkenylene, or when the L is substituted or unsubstituted C₂₋₁₀alkynylene, the C₂₋₁₀ alkynylene in the substituted or unsubstitutedC₂₋₁₀ alkynylene is C₂₋₅ alkynylene; or when the L is substituted orunsubstituted C₃₋₁₀ cycloalkylene, the C₃₋₁₀ cycloalkylene in thesubstituted or unsubstituted C₃₋₁₀ cycloalkylene is C₃₋₈ cycloalkylene;or when the L is substituted or unsubstituted C₃₋₁₀ cycloalkenylene, theC₃₋₁₀ cycloalkenylene in the substituted or unsubstituted C₃₋₁₀cycloalkenylene is C₃₋₈ cycloalkenylene; or when the L is substituted orunsubstituted C₁₋₁₀ heteroalkylene containing heteroatoms, the C₁₋₁₀heteroalkylene in the substituted or unsubstituted C₁₋₁₀ heteroalkylenecontaining heteroatoms is C₁₋₆ heteroalkylene; or when the L issubstituted or unsubstituted C₂₋₁₀ heteroalkenylene, the C₂₋₁₀heteroalkenylene in the substituted or unsubstituted C₂₋₁₀heteroalkenylene is C₂₋₅ heteroalkenylene; or when the L is substitutedor unsubstituted C₂₋₁₀ heteroalkynylene, the C₂₋₁₀ heteroalkynylene inthe substituted or unsubstituted C₂₋₁₀ heteroalkynylene is C₂₋₄heteroalkynylene; or when the L is substituted or unsubstituted C₂₋₁₀heterocycloalkylene, the C₂₋₁₀ heterocycloalkylene in the substituted orunsubstituted C₂₋₁₀ heterocycloalkylene is C₂₋₅ heterocycloalkylene; orwhen the L is substituted or unsubstituted C₂₋₁₀ heterocycloalkenylene,the C₂₋₁₀ heterocycloalkenylene in the substituted or unsubstitutedC₂₋₁₀ heterocycloalkenylene is C₂₋₅ heterocycloalkenylene; or when the Lis a substituted or unsubstituted C₁₋₁₀ heteroarylene, the C₁₋₁₀heteroarylene in the substituted or unsubstituted C₁₋₁₀ heteroarylene isC₁₋₉ heteroarylene; or when the R is substituted or unsubstituted C₃₋₈alkyl, the C₃₋₈ alkyl in the substituted or unsubstituted C₃₋₈ alkyl isn-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; or when the R issubstituted or unsubstituted C₂₋₈ alkenyl, the C₂₋₈ alkenyl in thesubstituted or unsubstituted C₂₋₈ alkenyl is C₂₋₅ alkenyl; or when the Ris substituted or unsubstituted C₂₋₈ alkynyl, the C₂₋₈ alkynyl in thesubstituted or unsubstituted C₂₋₈ alkynyl is C₂₋₅ alkynyl; or when the Ris substituted or unsubstituted C₃₋₈ cycloalkyl, the C₃₋₈ cycloalkyl inthe substituted or unsubstituted C₃₋₈ cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or whenthe R is substituted or unsubstituted C₃₋₈ cycloalkenyl, the C₃₋₈cycloalkenyl in the substituted or unsubstituted C₃₋₈ cycloalkenyl iscyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenylor cyclooctenyl.
 5. The compound represented by formula 1 or thepharmaceutically acceptable salt thereof according to claim 1, wherein:the L is substituted or unsubstituted C₂₋₁₀ alkenylene, substituted orunsubstituted C₁₋₁₀ heteroalkylene, or not existed; or the R ishydrogen, methyl, benzyl, or substituted or unsubstituted C₃₋₈ alkyl. 6.The compound represented by formula 1 or the pharmaceutically acceptablesalt thereof according to claim 1, wherein: the L is —CH═CH—, —CH₂OCH₂—,—CH₂OCH₂CH₂OCH₂—, or L is not existed, or the R is hydrogen, methyl ortert-butyl.
 7. The compound represented by formula 1 or thepharmaceutically acceptable salt thereof according to claim 1, wherein,the compound represented by formula 1 or the pharmaceutically acceptablesalt thereof is selected from any one of the following compounds:


8. A compound or a pharmaceutically acceptable salt thereof, wherein,the compound is represented by the structure of formula 2:

wherein: L is as defined in claim 1; and cations are cations formed fromvarious inorganic and organic bases.
 9. The compound or thepharmaceutically acceptable salt thereof according to claim 8, wherein,the compound represented by formula 2, wherein: L is as defined in claim8; and the inorganic base in the cations formed by various inorganicbases and organic bases is sodium carbonate, sodium bicarbonate, sodiumhydroxide, potassium carbonate, calcium hydroxide, magnesium carbonate,magnesium hydroxide, ammonium hydroxide or zinc hydroxide; or theorganic base in the cations formed by various inorganic bases andorganic bases is amine compound, or natural or non-natural amino acidcompound.
 10. The compound or the pharmaceutically acceptable saltthereof according to claim 8, wherein, the compound represented byformula 2, wherein: the cation in the compound is


11. The compound or the pharmaceutically acceptable salt thereofaccording to claim 8, wherein, the compound represented by formula 2 isselected from any one of the following compounds:


12. A method for preparing the compound represented by formula 1 or thepharmaceutically acceptable salt thereof according to claim 1, wherein,comprising: in an organic solvent, under the action of a base and acatalyst, Ginkgolide B and the compound represented by formula 3 aresubjected to the ether-forming reaction as shown below to obtain thecompound represented by formula 1,

wherein, R and L are as defined in claim 1, and X is halogen.
 13. Themethod for preparing the compound represented by formula 1 or thepharmaceutically acceptable salt thereof according to claim 12, wherein:the X is fluorine, chlorine, bromine or iodine; or the organic solventis one or more of halogenated hydrocarbon solvents, ether solvents,ketone solvents, nitrile solvents and amide solvents; or the base isorganic base and/or inorganic base; or the catalyst is iodide; or themolar concentration of the Ginkgolide B in the organic solvent is 0.001to 1 mol/L; or the molar ratio of the Ginkgolide B to the compoundrepresented by formula 3 is 1:1 to 1:5; or the molar ratio of theGinkgolide B to the base is 1:1 to 1:10; or the molar ratio of theGinkgolide B to the catalyst is 1:1 to 1:5; or the reaction temperatureof the ether-forming reaction is the temperature at which the organicsolvent used is refluxed at normal temperature and atmospheric pressure.14. A method for preparing the compound represented by formula 2according to claim 8, wherein, the method comprises the steps of: in anorganic solvent, under the action of an acid or a base, the compoundrepresented by formula 1 is subjected to hydrolysis reaction as shownbelow to obtain a compound represented by formula 1 in which R ishydrogen; the compound represented by formula 2 is obtained bysalt-forming reaction between the compound and various bases;

wherein L and cation are as defined in claim 8; and R is substituted orunsubstituted C₁₋₈ hydrocarbonyl, the substituent in the substitutedC₁₋₈ hydrocarbonyl is one or more of halogen, hydroxyl, C₁₋₁₀ alkoxy,phenyl and C₁₋₁₀ alkyl.
 15. The method for preparing the compoundrepresented by formula 2 according to claim 14, wherein for thehydrolysis reaction: in an organic solvent, under the action of an acidor a base, the compound represented by formula 1 is subjected tohydrolysis reaction as shown below to obtain a compound represented byformula 1 in which R is H; or the base is inorganic base and/or organicbase; or the acid is inorganic acid and/or organic acid; or the organicsolvent is alcohol solvent and halogenated hydrocarbon solvent; or whenthe compound represented by formula 1 is subjected to the hydrolysisreaction under the action of the base, the molar ratio of the compoundrepresented by formula 1 to the base is 1:1 to 1:10; or when thecompound represented by formula 1 is subjected to the hydrolysisreaction under the action of the base, the reaction temperature of thehydrolysis reaction is the temperature at which the organic solvent usedis refluxed at normal temperature and atmospheric pressure; or when thatcompound represented by formula 1 is subjected to the hydrolysisreaction under the action of the base, the reaction time of the presentdisclosure is 1 to 5 hour; or when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the base,the molar concentration of the compound represented by formula 1 in theorganic solvent is 0.001 to 1 mol/L; or when the compound represented byformula 1 is subjected to the hydrolysis reaction under the action ofthe acid, the molar ratio of the compound represented by formula 1 tothe acid is 1:2 to 1:100; or when the compound represented by formula 1is subjected to the hydrolysis reaction under the action of the acid,the molar concentration of the compound represented by formula 1 in theorganic solvent is 0.001 to 1 mol/L; or when the compound represented byformula 1 is subjected to the hydrolysis reaction under the action ofthe acid, the reaction temperature of the hydrolysis reaction is 15 to25° C.; or when the compound represented by formula 1 is subjected tothe hydrolysis reaction under the action of the acid, the reaction timein the present disclosure is 1 to 5 hours.
 16. The method for preparingthe compound represented by formula 2 according to claim 14, wherein forthe salt-forming reaction; in an organic solvent, the compoundrepresented by formula 1 (R is hydrogen) is mixed with a base forsalt-forming reaction; or the base is selected from inorganic base ororganic base; or the organic solvent is alcohol solvent; or the molarconcentration of the compound represented by formula 1 (R is hydrogen)in the organic solvent is 0.01 to 0.1 mol/L; or the molar ratio of thecompound represented by formula 1 (R is hydrogen) to the base is 1:1 to3; or the reaction temperature is 15 to 40° C.; or the reaction time is1 to 4 hours.
 17. A pharmaceutical composition, wherein, thepharmaceutical composition comprises a therapeutically effective dose ofthe compound represented by formula 1 or the pharmaceutically acceptablesalt thereof according to claim
 1. 18. A method for preventing ortreating diseases related to platelet activating factor in a subject inneed thereof, comprising: administering an effective amount of thecompound represented by formula 1 or the pharmaceutically acceptablesalt thereof according to claim 1 to the subject, the disease related toplatelet activating factor is ischemic stroke, thrombosis, anginapectoris, cardiopulmonary infarction, and inflammation or asthma.
 19. Amethod for preventing or treating diseases related to plateletactivating factor in a subject in need thereof, comprising:administering an effective amount of the compound represented by formula2 according to claim 8 to the subject, the disease related to plateletactivating factor is ischemic stroke, thrombosis, angina pectoris,cardiopulmonary infarction, and inflammation or asthma.
 20. Apharmaceutical composition comprising a therapeutically effective doseof the compound represented by formula 2 according to claim 8.